1. Risk of bolus thrombolytics Shamir Mehta, MD Director, Coronary Care Unit McMaster University Medical Center Hamilton, Ontario Paul Armstrong, MD Professor of Medicine University of Alberta Hospital Edmonton, Alberta

2. Despite promising phase II studies, no bolus thrombolytic agent has demonstrated superior efficacy (reduced death/MI) compared with either TPA or SK These agents have been aggressively marketed as being “more convenient,” despite no data showing that this impacts on clinical outcomes In the absence of efficacy, safety becomes critically important because there is no risk/benefit ratio to consider Risk of bolus lytics -Mehta Background

3. Intracranial hemorrhage Most feared complication of thrombolytic therapy A complication of treatment rather than of the underlying disease process Usually a risk-benefit tradeoff (TPA vs SK in GUSTO 1) No single bolus thrombolytic trial was adequately powered to detect a 30% excess in ICH. -Mehta Risk of bolus lytics

4. To detect a 30% excess in ICH: Assume ICH rate of 1% 2 groups, 1:1 randomization, 90% power More than 50,000 patients would be required in a single trial to reliably detect a 30% excess in ICH -Mehta Risk of bolus lytics Power to detect ICH

5. Increased peak blood levels of bolus agents Cannon et al. Circulation 1998;98:2805-14 Plasma concentration (ng/ml) Time (Minutes) Risk of bolus lytics

6. Trials of bolus vs infusion thrombolytics Mehta et al. Lancet 2000;356:449-54

7. Bolus vs infusion: overall results Mehta et al. Lancet 2000;356:449-54 OutcomeORP ICH 1.25 Other stroke 0.94 Death1.01 Re-infarction 1.04 95% CI 0.51.01.5 Bolus better Infusion better 0.97-1.110.3 0.97-1.060.6 0.81-1.090.4 1.08-1.45 0.003 N=103,972 Risk of bolus lytics

8. ICH: bolus vs infusion StudyOR ISIS-31.250.93-1.68 INJECT 2.031.04-3.99 COBALT 1.380.86-2.22 GUSTO-III1.040.72-1.49 BIRD1.010.50-3.23 ASSENT-20.990.72-1.35 InTIME-II1.721.22-2.44 Total* 1.251.08 - 1.45 95% CI 0.01.02.03.04.0 Bolus betterInfusion better Odds Ratio N=103,972 Mehta et al. Lancet 2000;356:449-54 Risk of bolus lytics

9. Conclusions: Mehta Bolus thrombolytic agents are not associated with an efficacy advantage in terms of reduced death or reinfarction, but are associated with an increase in intracranial hemorrhage Physicians and policy makers should be informed about this excess risk when making therapeutic decisions regarding choice of thrombolytic agent Risk of bolus lytics

10. “Dr Mehta and his colleagues... have raised a false alarm about the use of bolus fibrinolysis based on what appears to be a statistical collage that obscures some facts.” Paul Armstrong Professor of Medicine University of Alberta Hospital Edmonton, Alberta Risk of bolus lytics False alarm

11. Why would one move to bolus thrombolysis? Are the properties of the fibrinolytics relevant? Is the dose relevant? Is the adjunctive therapy relevant? -Armstrong Questions for debate Risk of bolus lytics

12. ISIS 3: APSAC comparison revisited -Armstrong APSAC vs (SK + tPA) APSAC vs tPA Bolus better Infusion better 2.35 (1.55 to 3.56) 4.03.53.02.52.01.51.0.50.0 1.24 (0.93-1.66) 0.84 (0.62 -1.14) APSAC vs SK Risk of bolus lytics

13. rPA and TNK vs t-PA OR (95% CI) odds ratio for ICH relative to tPA.25 1.039 (0.722-1.495) 0.991 (0.725-1.354) 1.011 (0.796-1.285) 14 GUSTO III ASSENT II Combined -Armstrong Risk of bolus lytics

14. rPA and TNK vs TPA: Frequency or likelihood of an ICH is essentially identical rPA and TNK, which are in general use, are safe, effective, and provide important advantages Conclusions: Armstrong Risk of bolus lytics

15. Log Odds Ratio Bolus betterInfusion better 1.25 Mehta et al. Lancet 2000:356;1850 Excluding ISIS-3 2-0.51.51 Risk of bolus lytics ICH in bolus vs infusion therapy

16. 2-0.51.51 Log Odds Ratio Bolus better Infusion better 1.22 Versus alteplase Mehta et al. Lancet 2000:356;1850 Risk of bolus lytics ICH in bolus vs infusion therapy

17. 2-0.51.51 Log Odds Ratio Bolus betterInfusion better 2.19 Versus streptokinase 3 Mehta et al. Lancet 2000:356;1850 ICH in bolus vs infusion therapy Risk of bolus lytics

18. 2-0.51.51 Log Odds Ratio Bolus betterInfusion better 1.25 1.75 Same/similar agent Newer thrombolytic agent P=0.02 P=0.0001 Mehta et al. Lancet 2000:356;449-54 Risk of bolus lytics ICH in bolus vs infusion therapy

19. The same doses of UFH were included in the 2 groups in all 7 trials in the meta-analysis Any reduction in ICH would be observed in both groups, and the relative difference is likely to be maintained There is little randomized data confirming that efficacy is maintained with lower heparin dosing Clinical implications of medication errors have not been adequately addressed -Mehta Risk of bolus lytics Heparin dosing

20. The study was overdosed (120 KU.kg -1 ) There is a drug-drug interaction with a clear and excess partial thromboplastin time for 6 hrs after therapy Lowering heparin lowered ICH rate in both arms -Armstrong Risk of bolus lytics InTIME-II

21. ICH Rate InTIME II infusion alteplase0.62% bolus lanoteplase1.12% ASSENT II infusion alteplase0.94% bolus tenecteplase0.93% Risk of bolus lytics Effect of heparin InTIME II investigators, Eur Heart J 2000:21;2005

22. “The perseveration around the statistics without consideration of the unique aspects of the components of dose and adjunctive therapy and how modifications in that therapy modify the result fails to take into account the realities.” Paul Armstrong Professor of Medicine University of Alberta Hospital Edmonton, Alberta Risk of bolus lytics Perseveration on statistics

23. In GUSTO I, ISIS-3, and INJECT the agent with the greater higher specificity was associated with higher intracranial hemorrhage No reason to believe different in InTIME-II -Mehta Risk of bolus lytics Fibrin specificity

24. The meta-analysis was designed to inform clinicians, not to dictate clinical practice Physicians must know the data in order to weigh risk/benefits and make reasonable clinical decisions that benefit patients -Mehta Risk of bolus lytics Recommendations for practice

25. Must look on both sides of the confidence limits Bolus agents are different and influenced by adjunctive therapy. Bolus agents have helped move to earlier therapy and improved time to treatment Awaiting results from studies of bolus therapy in conjunction with GP IIb/IIIa inhibitors Risk of bolus lytics Final comments: Armstrong

26. Looking forward to the results of pre-hospital treatment of AMI Also awaiting GP IIb/IIIa inhibitors plus reduced dose bolus thrombolytics Despite the money and effort, bolus thrombolytics have not yet shown a clear superiority Risk of bolus lytics Final comments: Mehta